Lin Xiaoyuan, Fu Beibei, Xiong Yan, Xue Weiwei, Lu Xiaoxue, Wang Shiwei, Guo Dong, Kunec Dusan, Mao Xuhu, Trimpert Jakob, Wu Haibo
Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), Chongqing 400038, China.
Institute of Virology, Free University of Berlin, Berlin 14163, Germany.
iScience. 2024 Dec 9;28(1):111551. doi: 10.1016/j.isci.2024.111551. eCollection 2025 Jan 17.
Severe cases of COVID-19 are associated with immune responses that lead to a surge in inflammatory molecules, resulting in multi-organ failure and death. This significant increase in inflammatory factors is triggered by viral proteins. Open reading frame 8 (ORF8) has received particular attention as a unique accessory protein of SARS-CoV-2. In a previous study, we have examined the role of unconventionally released ORF8 during cytokine storm associated with SARS-CoV-2 infection. Here, after mass spectrometry analysis and gene knockout/knockdown in cell/hamster models, we further discovered that Yip1 interacting factor homolog B (YIF1B) directly translocates unglycosylated ORF8 into vesicles that mediate cargo transport; specifically, the α4 helix of YIF1B interacts with the β8 sheet. Blocking ORF8 unconventional secretion via YIF1B knockdown attenuates inflammation and yields reduced mortality. Our study suggests that YIF1B directs ORF8 translocation into an unconventional secretion pathway, which has significant implications for the pathogenesis and treatment of COVID-19.
重症 COVID-19 病例与免疫反应相关，这些免疫反应会导致炎症分子激增，从而导致多器官衰竭和死亡。炎症因子的这种显著增加是由病毒蛋白触发的。开放阅读框 8（ORF8）作为严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的一种独特辅助蛋白受到了特别关注。在先前的一项研究中，我们研究了非传统释放的 ORF8 在与 SARS-CoV-2 感染相关的细胞因子风暴中的作用。在此，经过质谱分析以及细胞/仓鼠模型中的基因敲除/敲低后，我们进一步发现，Yip1 相互作用因子同源物 B（YIF1B）直接将未糖基化的 ORF8 转运到介导货物运输的囊泡中；具体而言，YIF1B 的α4螺旋与β8折叠相互作用。通过敲低 YIF1B 来阻断 ORF8 的非传统分泌可减轻炎症并降低死亡率。我们的研究表明，YIF1B 将 ORF8 转运到非传统分泌途径中，这对 COVID-19 的发病机制和治疗具有重要意义。
